Diffuse Coronary Artery Disease Research Articles

NON–RESPONSE TO INCLISIRAN THERAPY IN THREE PATIENTS WITH STATIN INTOLERANCE: A CASE SERIES

Abstract Background Inclisiran is the first silencing–RNA therapy used to reduce LDL–C. It is also recommended in patients with statin intolerance. We describe a case series of three no–responder patients to inclisiran. Case Series 64–year–old man with medical history of type II diabetes mellitus, obesity, hypertension, chronic kidney disease (eGFR 38 ml/min/1.73 m^2), dyslipidemia and statin intolerance. In 2022 the coronary angiography showed diffuse atherosclerosis without significant stenosis. His LDL–c was 115 mg/dl. Rosuvatatin 10 mg was prescribed however it was withdrawn due myalgia. Inclisiran and ezetimibe were prescribed, however one, three and four months later his LDL–C was 96 mg/dl, 114 mg/dl, and 115 mg/dl respectively (Fig 1). Due to the lack of effect, lovastatin 20 mg was added after the third dose of inclisiran, reaching LDL–C levels of 100 mg/dl one month after the initiation of lovastatin. Inclisiran was withdraw (as well as statin due to myalgia) and evolocumab 140 mg was administrated three months later the last dose of inclisiran. Ten days after evolocumab, LDL value was 66 mg/dl. 60–year–old man with hypertension, obesity, and dyslipidemia (LDL 152 mg/dl) with a moderate cardiovascular risk (target LDL–C <70 mg/dl). Patient refused statin therapy because he was scared about myalgia. In October 2021 (first Italian patient out of clinical trial) inclisiran was administrated. However, LDL–C did not change one month after the first and the second dose (147 mg/dl and 134 mg/dl respectively, Fig1). Due to the inefficacy, inclisiran was withdraw and the combination rosuvastatin and ezetimibe 10/10 mg was started with a reduction in LDL–cholesterol levels (51 mg/dl) four months later. However, this treatment was withdrawn due to myalgia in favor of bempedoic acid. One month later LDL–C level was 79 mg/dl. 79–year–old woman with history of coronary revascularization. She was statin and ezetimibe–intolerant, so she was treated with alirocumab 150 mg (LDL–C 89 mg/dl). Since the treatment was ineffective to reach the LDL target values, alirocumab was stopped in favor to inclisiran. However, LDL values increased over the time reaching 103 mg/dl one month after the first dose and 120 mg/dl two months later the second dose (Fig1). Conclusion some patients may be no–responder to inclisiran. A polymorphism of the asialoglycoprotein receptors might be a possible reason. Statin intolerance may also affect inclisiran efficacy.

Influence of Pathophysiological Patterns of Coronary Artery Disease on Immediate Percutaneous Coronary Intervention Outcomes.

Diffuse coronary artery disease (CAD) impacts the safety and efficacy of percutaneous coronary intervention (PCI). Pathophysiological CAD patterns can be quantified using fractional flow reserve (FFR) pullbacks incorporating the pullback pressure gradient (PPG) calculation. This study aimed to establish the capacity of PPG to predict optimal revascularisation and procedural outcomes. This prospective, investigator-initiated, single-arm, multicentre study enrolled patients with at least one epicardial lesion with an FFR ≤ 0.80 scheduled for PCI. Manual FFR pullbacks were employed to calculate PPG. The primary outcome of optimal revascularisation was defined as a post-PCI FFR ≥ 0.88. 993 patients with 1044 vessels were included. The mean FFR was 0.68 ± 0.12, PPG 0.62 ± 0.17, and post-PCI FFR 0.87 ± 0.07. PPG was significantly correlated with the change in FFR after PCI (r=0.65, 95% CI 0.61-0.69, p<0.001) and demonstrated excellent predicted capacity for optimal revascularisation (AUC 0.82, 95% CI 0.79-0.84, p<0.001). Conversely, FFR alone did not predict revascularisation outcomes (AUC 0.54, 95% CI 0.50-0.57). PPG influenced treatment decisions in 14% of patients, redirecting them from PCI to alternative treatment modalities. Periprocedural myocardial infarction occurred more frequently in patients with low PPG (<0.62) compared to those with focal disease (OR 1.71, 95% CI: 1.00-2.97). Pathophysiological CAD patterns distinctly affect the safety and effectiveness of PCI. The PPG showed an excellent predictive capacity for optimal revascularisation and demonstrated added value compared to a FFR measurement.

One-Year Outcomes of Long Coronary Drug-Eluting Stents (≥40 MM) in Patients With Diffuse Coronary Artery Disease: Findings From a Tertiary Care Hospital in North India.

Background and objective Diffuse coronary artery disease (CAD) is associated with extensive involvement of coronary arteries, necessitating the useof long (≥40 mm) drug-elutingstents (DES) based on the lesion length. However, these long DES can lead to complications such as in-stent restenosis (ISR) and stent thrombosis. This study aimed to assess the safety, efficacy, and one-year clinical outcomes of using long DESin patients with diffuse CAD undergoing PCI at a tertiary care hospital in north India. Methodology Patients with diffuse CAD undergoingPCI with longDESbetween January 2017 and June 2022 were included in the study. Baseline characteristics were recorded, and patients were followed up telephonically or in the outpatient department (OPD) at one, three, six, and 12 months following the PCI. The primary endpointwas the target lesion failure (TLF) rate, with secondary endpoints constituting all-cause mortality, major adverse cardiovascular events (MACE), subacute stent thrombosis, and ISR. Results A total of 200 patients were recruited and followed up for one year. The median age of the patients was 58 years (range: 48.25-63 years), and 82% were men. The most frequently stented artery was the left anterior descending (LAD, 48%), followed by the right coronary artery (RCA, 36%). A total of 388 stents (mean: 1.94 ±0.79) were implanted, including both long and short stents. The mean length and diameter of long stents were 43.64 ±3.58 mm and 3 ±0.37 mm, respectively. At the one-year follow-up, patients undergoing PCI with long DES ≥40 mm had an overall TLF rate of 5%, all-cause mortality of 6% (12 patients), MACE of 6% (12 patients), subacute stent thrombosis of 4% (eight patients), and ISR of 1% (two patients).A large proportion of patients (90%) had an uneventful follow-up of up to a year. At the one-year follow-up, all 10 (5%)patients with a primary outcomehad a smallerstent diameterthan those without a primary outcome (2.5 ±0.25 mm vs. 3.03 ±0.35 mm, p=0.015). Conclusions Our results suggest that using extremely long stents (>40 mm) for diffuse coronary lesions is safe, efficacious, and associated with relatively low event rates. In addition, the stent diameter has a substantial correlation with the primary outcome. Further studies with larger sample sizes as well as longer follow-up periods are required to validate our findings.

Stronger vasoconstriction and weaker vasodilation in mesenteric arteries of Ossabaw than Göttingen minipigs before manifestation of metabolic syndrome

The metabolic syndrome predisposes and contributes to the development and progression of atherosclerosis. The minipig strain “Ossabaw” is characterized by a polygenic predisposition to develop metabolic syndrome and diffuse atherosclerosis in response to a hypercaloric atherogenic diet. The aim of this study was to investigate whether Ossabaw minipigs exhibit an altered vasomotor function even before they develop their diseased phenotype. Mesenteric arteries of adult Ossabaw (n=30) and Göttingen minipigs (n=40), a pig strain without genetic predisposition to a metabolic syndrome, were harvested postmortem, dissected, and mounted on a myograph for isometric force measurements. Maximal vasoconstriction to smooth muscle cell depolarization with potassium chloride (KClmax) was repeatedly induced (twice 0.6×10−1 mol/L and twice 1.2×10−1 mol/L). Cumulative concentration-response curves were determined in response to 1×10−9 -1×10−4 mol/L norepinephrine. Endothelium-dependent and -independent vasodilation were analyzed in response to carbachol and nitroprusside, respectively (1×10−9 - 1×10−4 mol/L, each) after pre-constriction by norepinephrine. The baseline diameter of mesenteric arteries from Ossabaw minipigs was smaller than that from Göttingen minipigs (329±20 vs. 435±11 μm), and mesenteric arteries of Ossabaw minipigs developed a higher baseline force of contraction than mesenteric arteries of Göttingen minipigs (6.2±0.7 vs. 3.6±0.3 mN). The maximal vasoconstrictor response to KCl was comparable between the minipig strains. Vasoconstriction in response to norepinephrine was more pronounced in Ossabaw than in Göttingen minipigs (143±9 vs. 108±6% KClmax). Endothelium-dependent vasodilation (46.4±5.5 vs. 16.0±3.0% of norepinephrine-induced preconstriction) and -independent vasodilation (36.7±4.9 vs. 2.3±0.6% of norepinephrine-induced preconstriction) were less pronounced in Ossabaw than in Göttingen minipigs. Neither the differences in baseline diameter nor in baseline developed force of contraction had any effect on the above data, as analyzed in retrospectively matched subsets of mesenteric arteries with a comparable baseline diameter or a comparable baseline developed force of contraction, respectively. Even before the development of metabolic syndrome, vasomotor function is shifted to more vasoconstriction and less vasodilation in Ossabaw minipigs, suggesting a genetic predisposition for the early development of vascular dysfunction. Thus, Ossabaw minipigs may be a suitable model to reflect the human situation of a heterogeneous, genetically determined primordial risk constellation for vascular dysfunction. This work was supported by the German Research Foundation [SFB 1116 B08 to G.H. and P.K.] and the European COST ACTION in CARDIOPROTECTION [CA16225 to G.H. and IG16225 to G.H. and P.K.]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Correction to: Intravascular Imaging Findings After PCI in Patients With Focal and Diffuse Coronary Artery Disease.

Correction to: Intravascular Imaging Findings After PCI in Patients With Focal and Diffuse Coronary Artery Disease.

Endarterectomy may be an effective additional treatment for three diffuse coronary artery disease complicated with diabetes.

In order to evaluate the clinical efficacy of coronary endarterectomy (CE) and coronary artery bypass grafting (CABG) in patients with diabetes complicated with three diffuse coronary artery stenosis. A retrospective analysis was conducted on 460 patients with diabetes mellitus and diffuse three-vessel coronary artery disease who underwent CABG in our department from September 2015 to December 2021. The patients were divided into two groups according to whether they underwent CE: the simple CABG group (group A, n = 254) and the CABG combined CE group (group B, n = 206). The perioperative outcomes, recurrent angina pectoris during 1-year follow-up, and the patency rate of the grafted vessel in coronary CT angiography were compared between the two groups. There was no significant difference in the 30days mortality rate between the two groups (2.3% vs 2.4%, p < 0.05). Group A had a shorter operation time [(3.55 ± 0.59) h versus (4.35 ± 0.65) h], less bypass grafts [(2.72 ± 0.83) versus (3.65 ± 0.72) vessels/case], a lower incidence of perioperative myocardial infarction (7.1% vs 12.6%), and a lower number of patent graft vessels at 1-year follow-up [(2.15 ± 0.42) versus (2.88 ± 0.68) vessels/case] compared with group B (all p < 0.05). Group A had a higher incidence of recurrent angina during follow-up (14.49% vs 6.47%) (p < 0.05). Although there was no significant difference in the incidence of MACCE events between the two groups, the probability of revascularization was higher in group A. Compared with single CABG, combined CE in patients with diabetes mellitus and diffuse three-vessel coronary artery disease can achieve more complete revascularization, reduce the recurrence of angina pectoris and the needing of postoperative revascularization, but the incidence of perioperative myocardial infarction is higher.

Early tirofiban versus heparin for bridging dual antiplatelet therapy in patients undergoing coronary endarterectomy combined with coronary artery bypass grafting: a multicenter randomized controlled trial protocol (the THACE-CABG trial)

BackgroundFor complete revascularization, patients with diffuse coronary artery disease should have a coronary endarterectomy and a coronary artery bypass graft (CE-CABG). Sadly, CE can lead to a lack of endothelium, which raises the risk of thrombotic events. Even though daily dual antiplatelet therapies (DAPT) have been shown to reduce thrombotic events, the risk of perioperative thrombotic events is high during the high-risk period after CE-CABG, and there is no consistent protocol to bridge DAPT. This trial aims to compare safety and efficacy between tirofiban and heparin as DAPT bridging strategies after CE-CABG.MethodsIn phase I, 266 patients undergoing CE-CABG will be randomly assigned to tirofiban and heparin treatment groups to compare the two treatments in terms of the primary safety endpoint, chest tube drainage in the first 24 h. If the phase I trial shows tirofiban non-inferiority, phase II will commence, in which an additional 464 patients will be randomly assigned. All 730 patients will be studied to compare major cardiovascular and cerebrovascular events (MACCEs) between the groups in the first 30 days after surgery.DiscussionGiven the possible benefits of tirofiban administration after CE-CABG, this trial has the potential to advance the field of adult coronary heart surgery.Trial registrationchictr.org.cn, ChiCTR2200055697. Registered 6 January 2022. https://www.chictr.org.cn/com/25/showproj.aspx?proj=149451. Current version: 20,220,620.

One-year outcomes after off-pump coronary artery bypass grafting in diffuse coronary atherosclerosis

One-year outcomes after off-pump coronary artery bypass grafting in diffuse coronary atherosclerosis

Influence of intracoronary hemodynamic forces on atherosclerotic plaque phenotypes

Background and aimsCoronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition. MethodsProspective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained. ResultsOne hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56–0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30–0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6–24.3] vs. 7.03 [4.8–11.7] Pa, p < 0.001) and TSVI (163.9 [117.6–249.2] vs. 76.8 [23.1–140.9] m−1, p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00–1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19–9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11–7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002). ConclusionsFocal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features. Clinical trial registrationhttps://clinicaltrials,gov/ct2/show/NCT03782688

Very long versus overlapping drug eluting stents for the management of long coronary artery lesions

Background The prevalence of long diffuse coronary artery disease (CAD) is increasing nowadays due to increase prevalence of multiple risk factors and population ageing. We aimed in our study to show the differences clinically or angiographically (guided by IVUS) between the use of single long stent versus overlapping stents in very long coronary lesions (≥40 mm) in patients presented with chronic coronary syndromes. Methods 550 patients presenting with chronic coronary syndromes were included: 320 treated with a single long stent (≥40 mm) and 230 patients with two or more overlapping stents. Angiographic follow-up (guided by IVUS) 6 months after PCI was performed only in 50 patients. We assessed the procedural characteristics and the occurrence of major adverse cardiovascular events (MACE) after a median follow-up of 24 months. Results Total stent length was 56.16 ± 14.85 mm and mean diameter was 3.05 ± 0.36 mm. At the end of follow-up, MACE rate in the single long stent group was 4.1% vs. 7.8% in the overlapping stents group, with higher incidence in overlapping stents group but non-statistically significant (p value = 0.059). PCI using overlapping stents consumed more contrast volume (248 ± 85.36 vs 164.5 ± 70.43 ml, p < 0.001), and higher fluoroscopy time (23.65 ± 9.19 vs 19.72 ± 9.19 min, p < 0.001). Regarding IVUS subgroup follow-up, there was no significant difference between both groups regarding in-stent restenosis and MACE. Conclusions We can conclude that long or overlapping stents are both acceptable therapeutic choices for patients with long CAD. There was no difference between both strategies regarding angiographic follow-up guided by IVUS after 6 months.

Long-term benefits of drug-coated balloons for coronary artery revascularization.

Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) represents the treatment of choice for the majority of patients with coronary artery disease. While currently available DES, in addition to physiological support, has failed to show the non-inferiority to coronary artery bypass grafting (CABG) in terms of cumulative incidence of clinical events over the short-term follow-up. Studies have also shown that DES is associated with an increased risk of target vessel revascularization compared to CABG after long-term follow-up. Drug-coated balloons (DCB) have been shown to provide clinically significant benefits in the management of in-stent restenosis and diffuse coronary artery disease, as well as small coronary artery lesions. The aim of this review was to describe the inherent technical limitations of DES and highlight the potential advantages of PCI with DCB for long-term outcomes and potentially demonstrate its non-inferiority to CABG. Currently, ongoing studies will provide more information and help to understand if a blended therapy of DCB+DES can match the performance of CABG in the need for revascularization in more complex patients.

Preprocedural physiological assessment of coronary disease patterns to predict haemodynamic outcomes post-PCI.

Even with intracoronary imaging-guided stent optimisation, suboptimal haemodynamic outcomes post-percutaneous coronary intervention (PCI) can be related to residual lesions in non-stented segments. Preprocedural assessment of pathophysiological coronary artery disease (CAD) patterns could help predict the physiological response to PCI. The aim of this study was to assess the relationship between preprocedural pathophysiological haemodynamic patterns and intracoronary imaging findings, as well as their association with physiological outcomes immediately post-PCI. Data from 206 patients with chronic coronary syndrome enrolled in the ASET-JAPAN study were analysed. Pathophysiological CAD patterns were characterised using Murray law-based quantitative flow ratio (μQFR)-derived indices acquired from pre-PCI angiograms. The diffuseness of CAD was defined by the pullback pressure gradient (PPG) index. Intracoronary imaging in stented segments after stent optimisation was also analysed. In the multivariable analysis, diffuse disease - defined by the pre-PCI μQFR-PPG index - was an independent factor for predicting a post-PCI μQFR <0.91 (per 0.1 decrease of PPG index, odds ratio 1.57, 95% confidence interval: 1.07-2.34; p=0.022), whereas the stent expansion index (EI) was not associated with a suboptimal post-PCI μQFR. Among vessels with an EI ≥80% and post-PCI μQFR <0.91, 84.0% of those vessels had a diffuse pattern preprocedure. There was no significant difference in EI between vessels with diffuse disease and those with focal disease. The average plaque burden in the stented segment was significantly larger in vessels with a preprocedural diffuse CAD pattern. A physiological diffuse pattern preprocedure was an independent factor in predicting unfavourable immediate haemodynamic outcomes post-PCI, even after stent optimisation using intracoronary imaging. Preprocedural assessment of CAD patterns could identify patients who are likely to exhibit superior immediate haemodynamic outcomes following PCI.

Cost-effectiveness analysis of PCI in focal and diffuse coronary artery disease

Abstract Aims The pattern of CAD predicts angina relief after PCI. Our aim was to evaluate the cost-effectiveness of PCI in diffuse coronary artery disease (CAD) to deferral from PCI in these patients. Methods This is a sub-analysis of the TARGET-FFR randomized clinical trial (NCT03259815). The pullback pressure gradient (PPG) was calculated to differentiate focal from diffuse CAD. Healthcare resource use associated with the index hospitalization and with follow-up outpatient visits, medications, was recorded prospectively. We did not discount costs because of the limited follow-up period. Costs of procedures and follow-up consultations were derived from Healthcare Resource Group reference costs and drug costs from the National Health Service (NHS). Quality-adjusted life-years (QALYs) were derived from health-related quality of life and survival during the 3-month time horizon of the trial. Quality-of-life indexes (utilities) were evaluated at baseline and 3 months with the European Quality of Life–5 Dimensions (EQ-5D) instrument with UK weights scaled from 0 (death) to 1 (perfect health). The overall QALYs for each patient were estimated as the area under the curve determined by the utility values at baseline and 3 months. We computed confidence intervals for differences in costs and QALYs and in the incremental cost-effectiveness rate (ICER) using the bootstrap technique with the percentile method with 10 000 replications. A Markov model was used to simulate deferral of diffuse disease from PCI and not using PPG to select treatment. Probabilistic sensitivity analysis was undertaken to test the robustness of results to parameter uncertainty. Results Patients who underwent PCI for focal CAD had higher EQ-5D index values at follow-up (0.89 ± 0.18 vs 0.76 ± 0.28, p=0.004) and higher QALYs after 3 months follow-up (0.19 ± 0.06 vs 0.21 ± 0.04, p=0.022). Mean cumulative costs were £1574.3 ± 230.5 and significantly higher in patients treated for diffuse CAD as compared to patients treated for focal CAD (£1697 ± 293.4 vs £1393 ± 264.3; p&amp;lt;0.001). The ICER was £7746/QALY (95% CI 5024 – 11007). PCI in focal CAD saved £1522.2/QALY when compared to PCI in diffuse CAD (£7009.2 ± 1919.4 /QALY vs. £8531.4±2753.4 /QALY, p&amp;lt; 0.001). Deferring 30% of the diffuse CAD patients from PCI to optimized medical therapy would save £673.8/QALY (£7072.2 ± 1730.147 /QALY vs. £7746 ± 1943.5/QALY, p&amp;lt; 0.001). Conclusion PCI is more cost-effective in focal than diffuse CAD. Treatment of diffuse CAD results in worst QALYs and costlier procedures. Every 5% of the diffuse CAD patients that were deferred from PCI saved aproximately £100/QALY. Further trials are needed to determine if the cost-effectiveness of PCI can be improved by deferring patients with diffuse CAD.Quality of life in focal and diffuse CADCost-effectiveness focal vs diffuse CAD

Does the pre-procedural pathophysiological pattern impact post-procedural hemodynamic outcomes and vessel prognosis in multivessel coronary artery disease?

Abstract Aim The pathophysiological pattern of coronary artery disease (CAD) pre-procedure may affect the physiological response to percutaneous coronary intervention (PCI). The aim of this study was to evaluate whether the pathophysiological pattern of CAD, derived from virtual pullbacks of angiography-based fractional flow reserve, impacted the immediate hemodynamic outcome post-PCI. Methods and results Among 503 consecutive patients with chronic coronary syndrome and non-ST elevated acute coronary syndrome treated at least 1 vessel in the Multivessel TALENT trial, 826 quantitative flow ratio (QFR) analysable vessels were enrolled. Pre-procedural pathophysiological patterns in CAD were characterized by the physiological distribution and local severity of coronary atherosclerosis using QFR-derived indexes acquired from pre-PCI angiograms. The physiological distribution of CAD was defined as "predominant diffuse" or "focal" according to a QFR pullback pressure gradient (PPG) index &amp;lt;0.78 and ≥0.78, respectively. Physiological local severity was assessed using QFR gradient per 1 mm (dQFR/ds), with a value ≥ 0.025/mm defining the presence of a "major gradient". The optimal post-PCI QFR value was defined as QFR ≥0.91. Among the 826 vessels, 673 vessels were analysed (excluding vessels which have total occlusions, ostial lesions, and paired QFR not analysable). Mean pre-PCI PPG index was 0.70 with a nadir in the distribution curve. As per the definition, "focal" lesions were 30% of the total analysed vessels and 88% had a "major gradient". The majority of the vessels belong to predominantly diffuse disease with a major gradient (62.7%, Figure 1). Compared to predominantly focal disease with a major gradient, predominantly diffuse disease had a higher risk of a post-PCI QFR &amp;lt;0.91 (OR 1.78, 95%CI 1.23-2.58). The scatterplot between pre-procedural PPGI and post-procedural QFR showed positive correlation (Piason’s R=0.163, p&amp;lt;0.001, Figure 2). The correlation suggested that the vessels with focal lesions more frequently achieved optimal post-PCI QFR values compared to that with diffuse lesions. In multivariable analysis, low QFR PPG index (diffuse disease) was an independent factor for predicting a post-PCI QFR&amp;lt;0.91 (per 0.1 decreases of QFR PPG index, OR:10.3, 95% CI 1.7-63.3, p=0.012). The estimated 2-year VOCE, the powered secondary endpoint of this study, estimated by the post-QFR is 5.9% in treated vessels with predominant diffuse lesion, while 4.9% in that with predominant focal lesion based on the previous substudy of SYNTAX II trial.[1] Conclusions A physiological pattern of diffuse CAD pre-procedure was an independent factor in predicting an unfavourable immediate hemodynamic outcome post-PCI. Pre-procedural PPG index can be the predictor of not only post-PCI physiological value but also vessel base prognosis.pre-PCI pathophysiological patternScatterplot and correlation

Association between pre-procedural pathophysiological pattern of coronary disease and immediate hemodynamic outcome post-percutaneous coronary intervention

Abstract Background The pathophysiological pattern of coronary artery disease (CAD) pre-procedure may affect the physiological response to percutaneous coronary intervention (PCI). Purpose The aim of this study was to evaluate whether the pathophysiological pattern of CAD, derived from virtual pullbacks of angiography-based fractional flow reserve, was predictive of the immediate hemodynamic outcome post-PCI. Methods Data from 206 patients with chronic coronary syndrome enrolled in the ASET (Acetyl Salicylic Elimination Trial) JAPAN study were analyzed. The ASET JAPAN study is a multi-center, single-arm, open-label, proof-of-concept trial to demonstrate the feasibility and safety of "aspirin-free" therapy with low-dose prasugrel (3.75 mg) monotherapy following PCI, Pre-procedural pathophysiological patterns in CAD were characterized by the physiological distribution and local severity of coronary atherosclerosis using Murray law-based quantitative flow ratio (µQFR)-derived indexes acquired from pre-PCI angiograms. The physiological distribution of CAD was defined as "predominant diffuse" or "focal" according to a µQFR pullback pressure gradient (PPG) index &amp;lt;0.78 or ≥0.78, respectively. Physiological local severity was assessed using µQFR gradient per 1 mm (dµQFR/ds), with a value ≥ 0.025/mm defining the presence of a "major gradient". The statistical association of preprocedural pathophysiological pattern of CAD with post-PCI µQFR &amp;lt;0.91 was investigated. Results Out of 207 vessels, 26.6% (n=55) were classified as predominantly focal (µQFR PPG index ≥0.78) with a major gradient (dµQFR/ds ≥0.025/mm, Group 1), 1.0% (n=2) predominantly focal without a major gradient (Group 2), 53.6% (n=111) predominantly diffuse (µQFR PPG index &amp;lt;0.78) with a major gradient (Group 3), and 18.8% (n=39) predominantly diffuse with no major gradient (Group 4)(Figure 1). Vessels with predominantly diffuse disease and no major gradient (Group 4) had significantly higher pre-PCI µQFR (mean difference, -0.163; 95%CI, -0.211 to -0.118) and lower post-PCI µQFR (mean difference, 0.031; 95% CI, 0.014 to 0.487; by bootstrapping using 2000 replications) than those with predominantly focal disease and major gradients (Group 1). Low pre-PCI µQFR values were significantly associated with an increased risk of a post-PCI µQFR &amp;lt;0.91 (Figure 2A). Similarly, low µQFR PPG index showed a significantly higher risk of a post-PCI µQFR &amp;lt;0.91 (Figure 2B). The highest dµQFR/ds had no significant impact on the risk of a post-PCI µQFR &amp;lt;0.91 (Figure 2C). In multivariable analysis, low µQFR PPG index (diffuse disease) was an independent factor for predicting a post-PCI µQFR &amp;lt;0.91 (per 0.1 decrease of µQFR PPG index, OR:1.68, 95% CI 1.17-2.46, p=0.005). Conclusions A physiological pattern of diffuse CAD pre-procedure was an independent factor in predicting an unfavorable immediate hemodynamic outcome post-PCI.

Abstract 17002: Platelet-Derived Purified Exosome Product to Treat In-Stent Restenosis Porcine Model

Introduction: Patients with coronary artery disease (CAD) not amenable to revascularization are reported to have a 3-year mortality &gt;14%. Advances in treatment modalities including medical management, rotational atherectomy, balloon lithotripsy, and drug-eluting stents work for focal disease but poorly treat diffuse CAD. In a porcine model of in-stent restenosis, we here evaluated whether a pro-angiogenic platelet-derived exosome product (PEP) could be delivered into the perivascular space to foster collateral vessel formation. Methods/Results: Cobalt chromium stents were placed and were oversized by 1 mm in the left anterior descending (LAD) and posterior descending arteries (PDA) of sus scrofa domesticus pigs. In-stent restenosis was angiographically visualized at the 2-month timepoint, with hemodynamic significance documented with fractional flow reserve (FFR) of &lt;0.8. To document feasibility of PEP delivery into the perivascular space, exosomes were labeled with a far-red fluorescent tag and delivered into the perivascular bed. Here, the Bullfrog® micro-infusion catheter was positioned either in the great cardiac vein or the middle cardiac vein and PEP was delivered with the microneedle pointed towards the LAD or the PDA. Biodistribution demonstrated exosome retention and uptake around cardiac veins. Using the Bullfrog® technique, PEP was delivered in the perivascular space adjacent to areas of significant coronary stenosis. Initial results 1-month post-treatment demonstrated improved FFR of treated stenotic vessels (from 0.68 to 0.85), while untreated vessels demonstrate no change from previous FFR measurement (from 0.79 to 0.78). Conclusions: Here, exosome-mediated angiogenesis in the perivascular space improved coronary blood flow, distal to areas of stenosis. In patients with diffuse CAD, delivery of biotherapy in cardiac veins running anatomically parallel to stenosed epicardial arteries provides a novel therapeutic opportunity to supplement the existing armamentarium of therapies available for in-stent restenosis.

Abstract 13805: Associations of Subclavian Artery Calcification With Future Cardiovascular Events and Death: The Multi-Ethnic Study of Atherosclerosis

Introduction: Atherosclerosis affects the upper limbs and may be a marker of diffuse atherosclerosis and increased risk for cardiovascular events. Hypothesis: Subclavian artery calcification (SAC) and thoracic aorta calcification (TAC) obtained by chest CT provide additional information about future CV events and death beyond coronary artery calcification (CAC) and CV risk factors. Methods: Chest CT scans of MESA participants (N = 2519) at exam 5 (2016-18) were interrogated for the presence and extent of SAC, TAC, and CAC. Proportional hazards regression was conducted for associations with incident total CVD events (n = 209), adjusted for age, race/ethnicity, and sex, then SAC, TAC, and CAC adjusted for demographics and each other, and finally adding adjustment for CV risk factors. Results: The mean age of the sample was 68.3±9.2 years; 48% were male, 27% Black, 13% Chinese, 22% Hispanic, 38% White. The prevalence of any calcification was 62% for SAC, while being 60 and 69% for TAC and CAC, respectively. Among those with any calcification, N and median Agatston score were SAC: 1704, 76; TAC: 1655, 152; CAC 1896, 135. CAC predicted future events in all models (Table). After adjustment for demographics, the ln(Agatston score +1) in each calcified vascular bed predicted future CVD. Mean±SD of the predictors were ln(SAC+1): 2.4±2.4, ln(TAC+1) 2.7±2.9 and ln(CAC+1) 3.1±2.6. SAC, but not TAC, was still predictive after mutual adjustment. SAC was marginally predictive (HR: 1.08, p = 0.06) when CV risk factors were also included in the model. Conclusions: Calcification was common in all 3 vascular beds, but there is no evidence that predictions using SAC and TAC are independent of CAC. We speculate that although the tendency to calcify is similar across vascular beds, CAC is most relevant for incident CVD.

Kidney Intrinsic Mechanisms as Novel Targets in Renovascular Hypertension.

Almost a hundred years have passed since obstruction of the renal artery has been recognized to raise blood pressure. By now chronic renovascular disease (RVD) due to renal artery stenosis is recognized as a major source of renovascular hypertension and renal disease. In some patients, RVD unaccompanied by noteworthy renal dysfunction or blood pressure elevation may be incidentally identified during peripheral angiography. Nevertheless, in others, RVD might present as a progressive disease associated with diffuse atherosclerosis, leading to loss of renal function, renovascular hypertension, hemodynamic compromise, and a magnified risk for cardiovascular morbidity and mortality. Atherosclerotic RVD leads to renal atrophy, inflammation, and hypoxia but represents a potentially treatable cause of chronic renal failure because until severe fibrosis sets in the ischemic kidney, it retains a robust potential for vascular and tubular regeneration. This remarkable recovery capacity of the kidney begs for early diagnosis and treatment. However, accumulating evidence from both animal studies and randomized clinical trials has convincingly established the inadequate efficacy of renal artery revascularization to fully restore renal function or blood pressure control and has illuminated the potential of therapies targeted to the ischemic renal parenchyma to instigate renal regeneration. Some of the injurious mechanisms identified as potential therapeutic targets included oxidative stress, microvascular disease, inflammation, mitochondrial injury, and cellular senescence. This review recapitulates the intrinsic mechanisms that orchestrate renal damage and recovery in RVD and can be harnessed to introduce remedial opportunities.

Integrated myocardial flow reserve (iMFR) assessment: optimized PET blood flow quantification for diagnosis of coronary artery disease.

Distinguishing obstructive epicardial coronary artery disease (CAD) from microvascular dysfunction and diffuse atherosclerosis would be of immense benefit clinically. However, quantitative measures of absolute myocardial blood flow (MBF) integrate the effects of focal epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. In this study, MFR and relative perfusion quantification were combined to create integrated MFR (iMFR) which was evaluated using data from a large clinical registry and an international multi-center trial and validated against invasive coronary angiography (ICA). This study included 1,044 clinical patients referred for 82Rb rest/stress positron emission tomography myocardial perfusion imaging and ICA, along with 231 patients from the Flurpiridaz 301 trial (clinicaltrials.gov NCT01347710). MFR and relative perfusion quantification were combined to create an iMFR map. The incremental value of iMFR was evaluated for diagnosis of obstructive stenosis, adjusted for patient demographics and pre-test probability of CAD. Models for high-risk anatomy (left main or three-vessel disease) were also constructed. iMFR parameters of focally impaired perfusion resulted in best fitting diagnostic models. Receiver-operating characteristic analysis showed a slight improvement compared to standard quantitative perfusion approaches (AUC 0.824 vs. 0.809). Focally impaired perfusion was also associated with high-risk CAD anatomy (OR 1.40 for extent, and OR 2.40 for decreasing mean MFR). Diffusely impaired perfusion was associated with lower likelihood of obstructive CAD, and, in the absence of transient ischemic dilation (TID), with lower likelihood of high-risk CAD anatomy. Focally impaired perfusion extent derived from iMFR assessment is a powerful incremental predictor of obstructive CAD while diffusely impaired perfusion extent can help rule out obstructive and high-risk CAD in the absence of TID.

Number of blood neutrophil granulocytes is associated with diffuse coronary involvement in patients with increased lipoprotein (a)

Aim. To assess the level of lipoprotein (a) (Lp(a)) and other lipid profile parameters, the composition of blood leukocytes in patients with focal and diffuse coronary atherosclerosis who underwent coronary artery bypass surgery (CABG), as well as to study the effect of Lp(a) on the activation of leukocytes in vitro.Material and methods. The study included 120 male patients (mean age, 67±5 years) with multivessel coronary artery disease after elective CABG surgery. According to the type of coronary artery involvement, patients were divided into groups of diffuse (n=77) and focal (n=43) atherosclerosis. In peripheral blood samples, the content of the main fractions of lipoproteins, including Lp(a), was determined. Activation of neutrophil granulocytes upon addition of Lp(a) was assessed in whole blood and in primary cell culture.Results. In patients with diffuse coronary stenosis, there was a tendency to higher Lp(a) levels; no changes in other lipid profile parameters were detected. In this group of patients, an increase in the absolute leukocyte count was noted due to neutrophilic granulocytes. An absolute neutrophil count &gt;2,9 million/mL was associated with diffuse disease (AUC, 0,69 (95% confidence interval (CI) 0,600,77), p=0,0002, sensitivity 85%, specificity 42%). In patients with Lp(a) ³30 mg/dL, the diagnostic value of a neutrophil count &gt;2,9 million/mL for diffuse stenosis was higher (AUC, 0,74 (95% CI 0,60-0,86), p= 0,005, sensitivity 90%, specificity 48%). According to logistic regression analysis with the introduction of neutrophils and conventional risk factors (age, body mass index, hypertension and smoking) into the model, only the number of neutrophils above the threshold level remained an independent factor in diffuse coronary stenosis. Lp(a) can induce neutrophil activation, detected by increased CD66b overexpression in whole blood, as well as the formation of neutrophil extracellular traps in primary cell culture.Conclusion. Neutrophil granulocytes can participate in the formation of diffuse atherosclerotic coronary lesions. One of the neutrophil activators may be Lp(a). The combination of high neutrophil count and Lp(a) level in the blood increases the risk of diffuse coronary atherosclerosis.